Remodeling of the airway epithelium is a common pathological feature in chronic lung disease and a predisposing factor in the development of lung cancer. Accordingly, understanding cellular and molecular mechanisms of epithelial maintenance and repair are fundamental to the development of improved therapeutic modalities for the treatment of chronic lung disease. Key findings from our earlier funding were that progenitor cell depletion results in the activation of latent airway stem cells to affect epithelial regeneration. The ensuing reparative process required tight regulation of stem cell proliferation, migration of nascent progenitor cells and regulation of cellular differentiation. These critical phases of epithelial regeneration were accompanied by stabilization of (-catenin and regulation of (-catenin/TCFdependent gene transcription. In this proposal we will test the hypothesis that activation of the Wnt/(-catenin signaling pathway in adult repairing airways is necessary for precise orchestration of cell proliferation, migration and differentiation among epithelial stem and progenitor cell pools. Three specific aims are proposed. Experiments in Aim 1 will investigate dynamic regulation of genes involved in regulation of the Wnt/(-catenin pathway and downstream target genes during repair of progenitor cell depleted airways. In Aim 2, we will use conditional transgenic/knock-out approaches to either potentiate or inhibit (-catenin signaling to define functional roles for pathway activation in the regulation of airway wound repair. Finally, direct roles for Wnt signaling in regulation of (-catenin stabilization and downstream signaling will be determined by interference with Wnt interaction with its bipartite LRP/Fzd receptor during airway injury and repair through conditional expression of a dominant secreted inhibitor, Dkk1. Completion of these aims will provide new insights into signaling mechanisms responsible for epithelial regeneration and remodeling in the normal and diseased lung, and identify new targets that may be exploited for therapeutic intervention.